Apoptosis is a cell suicide mechanism that is used by multicellular organisms to regulate physiological cell death for purposes of defense, development, homeostasis and aging. Apoptosis is an active process modulated by its own regulatory system and genetics and is generally characterized by morphological changes including loss of contact of a cell with its neighbors, chromatin condensation, membrane blebbing, cytoplasmic condensation, DNA fragmentation and, eventually, the generation of membrane-enclosed apoptotic bodies that are phagocytosed by neighboring cells.
CD95 (also referred to as Fas or APO-1) is an important receptor in apoptosis. Apoptotic cell death is triggered by an interaction of the CD95 receptor with its ligand CD95L. CD95 is a member of the tumor necrosis factor (TNF) receptor family of cell surface proteins, and CD95L is a member of the TNF family of membrane and secreted proteins. CD95 is expressed on a wide variety of cell types, either constitutively or inducibly. CD95 is expressed, for example, on activated T and B cells, and its mRNA has been detected in other tissues including thymus, spleen, liver, ovary, lung, and heart.
CD95 has been implicated in mediating nonspecific T-cell cytotoxicity and activation-induced cell death (AICD) in the peripheral immune system. When apoptosis is induced in T cells by activation through an antigen receptor, signals are passed into the cell, leading to activation of the cell and expression of c-myc. The cell up-regulates both CD95 and CD95L and expresses them on the cell surface. These molecules then interact with each other, in an autocrine or paracrine manner, initiating the cell death-inducing signaling pathway. Overexpression of CD95 receptor signaling domain results in apoptosis and cell death.
Regulating apoptosis has therapeutic and/or prophylactic implications for diseases where apoptosis causes the pathology, including chronic neurodegenerative disorders such as Alzheimer's and Parkinson's diseases and multiple sclerosis, and immunosuppressive disorders, both genetic and acquired. Similarly, regulating apoptosis may have therapeutic benefits under circumstances in which apoptosis occurs as a result of trauma, such as strokes and heart attacks. Agents that block apoptosis may be useful in treating ischemic conditions, such as heart attacks, strokes or reperfusion injury, by blocking the apoptotic response in cells. Pathological suppression of apoptosis appears to be an important factor in neoplastic diseases and viral infection. Apoptosis is suppressed, for example, in proliferating tumor cells. HIV/AIDS infection produces unregulated and untimely apoptosis in crucial defenders of the immune system, namely CD-4 cells. Moreover, modulation of apoptosis may increase tolerance to pharmaceutical agents such as chemotherapeutic and radiotherapeutic agents that stress but, absent an apoptotic mechanism, may not kill cells. Regulation of apoptosis may also have implications for in vitro cell growth and maintenance and may be used to produce more robust cell lines and increase production of recombinant proteins.
The numerous applications in which regulation of apoptosis may play an important role underscore the importance of developing a more complete understanding of expression of the CD95 receptor. Identification of regulatory sequences on the CD95 gene, as well as transcription factors that bind to such regulatory sequences, will provide means for modulating transcription and expression of this important receptor, thereby providing a means to regulate apoptosis.